Synthesis of Lactams via Isocyanide-Based Multicomponent Reactions

This review is dedicated to Albert Einstein

Abstract

Lactams are very important heterocycles as a result of their presence in a wide range of bioactive molecules, natural products and drugs, and also due their utility as versatile synthetic intermediates. Due to these reasons, numerous efforts have focused on the development of effective and efficient methods for their synthesis. Compared to conventional two-component reactions, multicomponent reactions (MCRs), particularly isocyanide-based MCRs, are widely used for the synthesis of a range of small heterocycles including lactam analogues. Despite their numerous applications in almost every field of chemistry, as yet there is no dedicated review on isocyanide-based multicomponent reactions (IMCRs) concerning the synthesis of lactams. Therefore, this review presents strategies towards the synthesis of α-, β-, γ-, δ- and ε-lactams using IMCRs or IMCRs/post-transformation reactions reported in the literature between 2000 and 2020.

1 Introduction

2 Developments in Lactam Synthesis

2.1 α-Lactams

2.2 β-Lactams

2.3 γ-Lactams

2.3.1 General γ-Lactams

2.3.2 Benzo-Fused γ-Lactams

2.3.3 Spiro γ-Lactams

2.3.4 α,β-Unsaturated γ-Lactams

2.3.5 Polycyclic Fused γ-Lactams

2.4 δ-Lactams

2.5 ε-Lactams

3 Conclusions

Key words

lactam synthesis - isocyanides - isocyanide-based multicomponent reactions - post-transformations - cyclic amides

Biographical Sketch

Shrikant G. Pharande was born in Maharashtra, India in 1987. He obtained his B.Sc. and M.Sc. degrees (Tuljaram Chaturchand College, Baramati) in chemistry from Pune University. Later, he worked as a research assistant at the National Chemical Laboratory, Pune with Dr. Hanumant Borate and Dr. Vandana Pore for two years. In 2014, he started his doctoral studies under the supervision of Professor Dr. Rocio Gámez-Montaño at the University of Guanajuato, Guanajuato, Mexico and received his Ph.D. degree in 2018.

1

Introduction

Since the discovery of the penicillin antibiotics 1 (Figure [1]) by Alexander Fleming,[1] β-lactams and their analogues have become very important in numerous areas of medicinal chemistry and drug discovery. Lactams are cyclic amides that are generally categorized based on their ring size. The three-, four-, five, six- and seven-membered rings are named α-lactam 2 (also known as 2-aziridinones), β-lactam 3 (2-azetidinones), γ-lactam 4 (2-pyrrolidinones), δ-lactam 6 (2-piperidinones) and ε-lactam 7 (2-azepanones or caprolactam), respectively (Figure [1]).

Figure 1 General structure of penicillin 1 and ring variants of lactam heterocycles 2–6

Lactams are recognized as a privileged class of heterocycles, and apart from their antibiotic properties,[2] this core is present in many bioactive molecules. Many lactam-containing compounds possess useful biological activity, specifically with three- to seven-membered-ring lactams representing some of the most important. Examples of such activity are β-lactamase inhibition, cholesterol absorption inhibition,[3a] antimicrobial,[3`] [c] [d] antifungal,[4] antimalarial,[5] anti-HIV,[6] anticancer,[7] anti-inflammatory,[8] antidepressant,[9] antiviral,[10] DPP-4 inhibition[11] and anticonvulsant.[12] Additionally, lactams are very important structural motifs present in several natural products such as the penicillins 1 (Figure [1]), nocardicin A (7), monobactam (8), tabtoxin (9), pseurotin A (10), dysidin (11), sintokamides A–E (12), malingamide A (13), strychnine (14), adalinine (15), corydaidine (16), caprolactin A (17), isobenganamide E (18) and bengamide K (19) (Figure [2]).[13]

β-Lactams constitute a major class of antibiotics and contribute to more than 50% of the global antibiotics market. However, due to increasing antibacterial resistance toward β-lactam antibiotics,[14] the scientific community has been forced to move its focus from four-membered lactam rings to other larger-ring lactam analogues. In this context, in 1986, two independent research groups reported for the first time the synthesis of γ-lactam-based antibiotics.[15] Unfortunately, none of them showed prominent biological activity as antibacterials or as β-lactamase inhibitors. However, these results encouraged many academics and industrial researchers to plan synthetic routes to develop new bioactive compounds containing larger ring-sized analogues of β-lactam. As a result, numerous synthetic methodologies have been described for the synthesis of β-lactams and their analogues.

Figure 2 Natural products containing a lactam core

Of the various approaches towards lactams, the isocyanide-based multicomponent reaction (IMCR) is one of the most diverse, versatile, and widely used methods.[16] The first IMCR was described by Passerini in 1921 involving a three-component reaction between carboxylic acids, oxo compounds, and isocyanides to afford α-acyloxy carboxamides in one-step.[17] This reaction was further expanded by Ugi et al. in 1959 as a four-component variant by using amines as the fourth component to give a diamide product.[18] Shortly after, the same group reported the first synthesis of a β-lactam using their reaction methodology.[19] IMCRs, especially Ugi-four component (Ugi-4CR) and Ugi-three component reactions (Ugi-3CR), are perfectly suited for the synthesis of lactam-like small molecules since they allow the construction of complex products using small and simple building blocks in a single operation, or may lead to a product containing multifunctional groups which can be used as a substrate for another complexity-generating reaction.[20] Also, during the Ugi reaction an intramolecular Mumm rearrangement occurs resulting in the facile formation of small cyclic products via ring closure.

In the last two decades, several articles discussing the formation of a variety of lactams via IMCRs have been published, thus illustrating their importance in various fields of interest, particularly in medicinal chemistry. However, there is no single dedicated review that describes the synthesis of α-, β-, γ-, δ- and ε-lactams using IMCRs. Thus, the present review specifically focuses on the synthesis of the abovementioned five classes of lactams containing only a single amide bond via IMCR or IMCR/post-transformation strategies, and excludes synthetic methods towards the synthesis of lactams possessing bis-amide bonds such as diketopiperazines. This review covers the major contributions from the literature between 2000 and 2020, with minor exceptions, and describes only three to seven-membered ring-sized lactams.

2

Developments in Lactam Synthesis

2.1

α-Lactams

An α-lactam is a highly strained three-membered heterocycle which can undergo ring-opening in the presence of any nucleophile. For these reasons, their facile and efficient synthesis has been a challenge for many organic chemists. Traditionally α-lactams are prepared by cyclization of α-haloamides mediated by a strong base,[21] however, unwanted side reactions resulting from the use of a strong base are always a concern. In this context, Qian and co-workers reported[22] the base-free synthesis of monofluorinated α-lactams 21 and 22 via a one-pot IMCR followed by an intramolecular cyclization strategy (Scheme [1]). A small series of α-lactam products 22 was prepared in moderate to good yields of 45–67% via the Ugi-4CR between gem-difluoromethylene isocyanide 20 with aldehydes, amines, and acids followed by dehydrofluorination under solvent-free heating conditions. On the other hand, α-lactam 21 was synthesized via an Ugi-3CR/intramolecular cyclization in MeOH at room temperature or under reflux conditions.

Scheme 1 Synthesis of monofluorinated α-lactams 21 and 22

2.2

β-Lactams

Ding and co-workers[23] developed an efficient route for the synthesis of β-lactams 26 in moderate to excellent yields via a one-pot Ugi-4CR/S_N cyclization strategy (Scheme [2]). The authors reacted substituted phenyl glyoxal 23 and α-bromocarboxylic acid (24) with various amines and isocyanides to give Ugi intermediate 25 along with β-lactam 26 in low yield. The intramolecular substitution happened with the release of HBr and resulted in a drop of pH from 7 to 4. Thus, the authors used Cs₂CO₃ as a base to neutralize the reaction solution (pH 6) and to trigger the substitution reaction to give the final products 26 in higher yields.

Scheme 2 Ugi-4CR/S_N cyclization to obtain β-lactams 26

Lu and co-workers[24] reacted maleic or fumaric acid 27 with aldehydes, isocyanides, and amines to give β-lactams 30 via a one-pot Ugi-4CR/intramolecular Michael addition in methanol at 55 °C (Scheme [3]). According to DFT calculations, this reaction prefers a Michael addition path by generating anion 29 from Ugi adduct 28 instead of an aza-Michael route.[25] Furthermore, based on theoretical calculations, the authors noted that the diastereoselectivity was controlled by the Michael addition step. The advantage of this methodology is its robustness for synthesizing medicinally important β-lactams in one pot under mild conditions.

Scheme 3 Synthesis of β-lactams 30

Five examples concerning the synthesis of β-lactams 32 from bifunctional β-amino acids via an isocyanide-less IMCR method have been described (Scheme [4]).[26] The authors synthesized diverse formamides 31 by using a modified Leuckart–Wallach procedure, which were further converted in situ into isocyanides and reacted in the same pot with the respective aldehyde and β-amino acid via an Ugi-3CR to afford β-lactams 32 in moderate to excellent yields (49–90%). This new method resulted in higher yields of the desired products in shorter reaction times compared to the traditional method.

Scheme 4 Synthesis of β-lactams via an isocyanide-less IMCR

AnchorQuery, a build on scaffold-hopping technique,[27] is a pharmacophore-based virtual screening platform which allows the rapid and efficient screening of chemical libraries.[28] With the help of AnchorQuery, the research group of Dömling reported[29] the synthesis of β-lactams 36 in moderate to good yields via a two-step microwave-assisted Ugi-3CR followed by diastereomeric separation and hydrolysis (Scheme [5]). The multicomponent reaction between aldehyde 33, substituted amino acid 34, and an isocyanide at 130 °C under microwave irradiation resulted in the formation of β-lactam Ugi adduct 35 in a 1:1 diastereomeric ratio, which upon diastereomeric separation followed by ester hydrolysis using LiOH gave lactam 36. All the synthesized β-lactams were examined for their MDM2 receptor binding affinities using computational modeling methods. Among them, compound 36a was found to be the more potent with a 200 nM binding affinity to the MDM2 receptor.

Scheme 5 Synthesis of β-lactams 36

The group of Blackie has employed an Ugi-3CR to synthesize β-lactams 38 in good to excellent yields (64–84%) by using β-alanine (37), cyclohexyl isocyanide and a variety of aromatic aldehydes in MeOH at room temperature.[30] All the Ugi products are racemic mixtures and were screened in an in vitro assay against the chloroquine-sensitive D10 strain of Plasmodium falciparum. All the tested compounds showed low to moderate antimalarial activity (Scheme [6]).

Scheme 6 Synthesis of β-lactams 38 via an Ugi-3CR using β-alanine (37)

Rodríguez and Avilés discovered that the extracts of some marine sponges from Mona Island (Puerto Rico) exhibited antiplasmodial and antimycobacterial activity.[31] Large-scale organic extraction of 200 g of the dried sponge Svenzea flava using a 1:1 mixture of CHCl₃–MeOH resulted in the isolation of 3 mg of the diterpenoid β-lactam alkaloid monamphilectine A (40), along with 528 mg of the sesquiterpene isocyanide (–)-DINCA (39).[32] To confirm the relative and absolute configuration, and to investigate its bioactivity, a semisynthesis of monamphilectine A (40) was successfully performed in 61% yield via an Ugi-3CR of β-alanine, formaldehyde and isocyanide 39 in MeOH (Scheme [7]).[31] Both, monamphilectine A (40) and (–)-DINCA showed dual in vitro activity against the chloroquine-resistant W2 strain of P. falciparum (IC₅₀: 0.60 μM and 0.04 μM) and M. tuberculosis H37Rv (MIC values: 15.3 μg/mL and 3.2 μg/mL), respectively.

Scheme 7 Semisynthesis of the diterpenoid β-lactam alkaloid 40 via an Ugi-3CR

Silvani and co-workers[33] developed a strategy for the synthesis of β-lactam-core-linked oxindoles 43 via an Ugi-3CR using isatins 41, isocyanides, and β-amino acids 42 in a one-pot manner (Scheme [8]). When chiral β-amino acids 42a and 42b were used, enantiomerically pure β-lactam diastereoisomers 43a (dr = 63:37) and 43b (dr = 65:35) were obtained as the products, the relative stereochemistries of which were determined by X-ray analysis. Further, all the synthesized products were screened for antibacterial activity, however, only compound 43c showed weak activity.

Scheme 8 Synthesis of β-lactam-containing 3,3-disubstituted oxindoles 43 via an Ugi-3CR

Scheme 9 Synthesis of β-lactams via Ugi-3CRs in (a) water, and (b) 1 M aqueous glucose solution as a non-ionic solvent

The Ugi reaction can be carried out efficiently under aqueous conditions to give products in high yields.[34] Pirrung and Sarma[35] developed an Ugi-3CR using either substituted or unsubstituted β-amino acids 44 and a variety of aldehydes and isocyanides to give β-lactams 45 in good to excellent yields (71–89%) using water as a green solvent (Scheme [9, a]). All the products were isolated by extraction with high HPLC purity (70–99%). The same research group disclosed Ugi-3CR methodology to synthesize a series of acyclic and fused cyclic β-lactams 47 using β-keto acids 46 in 1 M aqueous glucose solution as a non-ionic solvent (Scheme [9, b]).[36] It was noted that due to the additional ring strain generated by four-membered lactams in the case of cyclic β-keto acids, lower yields were obtained with prolonged reaction times (6 days) compared to the acyclic β-keto acids (3 days).

Scheme 10 Synthesis of bi- and tricyclic β-lactams 50 via an Ugi-3CR

Scheme 11 Synthesis of heterocycle-linked α-methylene β-lactams 54 via Ugi-4CR/intramolecular addition reactions

In the same vein, a water-mediated synthetic route for the synthesis of bi- and tricyclic β-lactams 50 was developed by Fülöp and co-workers[37] using racemic cyclic β-amino acids 48 with aldehydes and isocyanides via an Ugi-3CR (Scheme [10]). The use of water as a solvent was found to be advantageous over organic solvents as all the products were isolated in high yields by either filtration or extraction.[38] The concentration of water in the reaction played an important role in the formation of the product. Additionally, the same research group developed an Ugi-3CR methodology to synthesize enantiopure tricyclic β-lactams using (1R,2R,3S,4R)-2-amino-6,6-dimethylbicyclo[3.1.1]heptane-3-carboxylic acid (49).[39] A comparative study of the effect of the reaction medium on the yields and time of the reaction was performed. A similar set of reactions was carried out in MeOH, in water and under neat conditions. The reactions in water were found to be more efficient and more rapid than in MeOH or under neat conditions.

α-Methylene β-lactam represents one type of important building block with numerous applications in the synthesis of medicinally active molecules and natural products.[40] Van der Eycken and co-workers have reported the synthesis of heterocycle-linked α-methylene β-lactams 54 in yields of up to 82% by employing Ugi adducts 53 containing substituted terminal alkynes in In(III)-catalyzed intramolecular addition reactions (Scheme [11]).[41] The adducts 53 were obtained by reacting heterocyclic aldehydes 51, acid 52, isocyanides, and amines via an Ugi-4CR in a sealed tube.

Scheme 12 Synthesis of β-lactams 57 via Ugi-4CR/cyclization reactions

Balalaie and co-workers demonstrated an efficient route for the synthesis of β-lactams 57 in good to excellent yields (63–95%) via a one-pot Ugi-4CR/base-mediated cyclization reaction (Scheme [12]).[42] A variety of aromatic and heteroaromatic aldehydes worked well in the reaction and gave excellent yields of the final products 57. Further, X-ray crystallographic data confirmed the E-configuration of the double bond. In 2018, Srivastava and co-workers[43] synthesized a similar series of β-lactams 57 by using an identical one-pot Ugi-4CR/intramolecular cyclization methodology starting from phenylpropiolic acid (55), aldehydes, isocyanides and amines to obtain Ugi adducts 56. This was followed by treatment with sodium hydride to facilitate the intramolecular cyclization resulting in the formation of β-lactams 57 (Scheme [12]). These authors screened all their synthesized β-lactams against the histamine-3 receptor (H3R), however, none of them were found to be active.

α-Substituted sulfonyloxy ketones 58 are efficient substrates for the synthesis of β-lactams 60 via a two-step Passerini-3CR followed by base-mediated cyclization (Scheme [13]).[44] The solvent-free reactions of compounds 58 with isocyanides and acids under a nitrogen atmosphere resulted in the formation of Passerini adducts 59 in quantitative yields. The adducts 59 were readily converted into β-lactams 60 via intramolecular cyclization in the presence of NaH (1.5 equiv). It was claimed that the sulfonyl ketone 58 underwent the Passerini condensation more rapidly than the parent aryl or aliphatic ketone.

Scheme 13 Synthesis of β-lactams 60

Scheme 14 Synthesis of β-lactams 64

In 2017, El Kaïm and co-workers[45] disclosed a novel two-step method towards the synthesis of β-lactams 64 via an Ugi-4CR followed by base-mediated [3+1] cyclization of amide dianions using diiodomethane (Scheme [14]). The authors reacted aldehydes, amines, isocyanides, and acids under conventional Ugi-4CR conditions to afford Ugi adducts 61 in up to quantitative yields, which under strongly basic conditions in the presence of diiodomethane were converted into β-lactams 64 at room temperature. The optimization studies revealed that 2.5 equivalents of NaH in DMSO were sufficient for the reaction between adduct 61 and CH₂I₂ to give the expected cyclized product 64. It was suggested, by DFT calculations, that anion 62 first reacts with CH₂I₂ to give iodomethyl Ugi intermediate 63, which then undergoes an intramolecular cyclization to yield product 64.

Later, in 2019, El Kaïm[46] reported the two-step synthesis of bis β-lactams 67 in poor to good yields (28–61%) via an Ugi-3CR followed by a base-mediated diiodomethane cyclocondensation reaction at room temperature (Scheme [15]). The amino acid 65 on reaction with an isocyanide and an aldehyde at 120 °C under microwave irradiation was readily converted into β-lactam 66. Next, NaH–CH₂I₂-based cyclocondensation afforded bis β-lactam 67. Also, it was demonstrated that two consecutive β-lactam formations could be achieved under one-pot conditions with comparable yields. All the synthesized bis β-lactams were screened for antibacterial activity against Escherichia coli MC4100, Staphylococcus aureus subsp. aureus ATCC6538 and Micrococcus luteus ATCC9341 strains, however, none of them were found to be active.

Scheme 15 Synthesis of bis β-lactams 67

2.3

γ-Lactams

Due to the availability of a large number of IMCR-based reports for the synthesis of γ-lactams, this section has been further subdivided into sections for a more detailed insight.

2.3.1

General γ-Lactams

In 2004, Tye and Whittaker[47] reported a rapid and efficient synthesis of γ-lactams 69 in poor to excellent yields (17–90%) via Ugi-3CRs of levulinic acid (68), amines, and isocyanides under MW heating conditions (Scheme [16], conditions a). The authors used a design of experiments (DoE) approach for rapid reaction optimization. It was claimed that this methodology enabled the synthesis of γ-lactams in just 30 minutes compared to the traditional process,[48] which required 48 hours. In the same vein, Mironov and co-workers[49] published a method to synthesize similar γ-lactams 69 using water and surfactant solutions as solvents (Scheme [16], conditions b). Mironov reported that even less soluble substrates reacted readily and gave the final γ-lactam products in good yields. In a parallel investigation, the rapid synthesis of γ-lactams 69 was reported by Deprez and co-workers[50] by employing acid 68 with a variety of isocyanides and amines under solvent-free microwave conditions (Scheme [16], conditions c). Quantitative yields (15 examples, 83–96%) were obtained in the majority of cases in just 3 minutes of reaction time. It was claimed that improved yields of cyclized products were obtained under MW heating compared to conventional methods. Similarly, in 2004, Krelaus and Westermann[51] synthesized γ-lactams 69 in poor to excellent yields via Ugi-3CRs using bifunctional acid 68 and isocyanides along with chiral and achiral amines (Scheme [16], conditions d).

Scheme 16 Syntheses of γ-lactams 69

γ-Lactams 72a–e (Scheme [17]), popularly known as racetams, are a large class of drugs used in the treatment of epilepsy, dementia, depression, anxiety, and hypoxia.[52] Thus, inspired by the medicinal importance of these small molecules and by the lack of simple and versatile methods towards their synthesis, the research group of Orru[53] published a mild and efficient method for the synthesis of γ-lactams 71 by employing amino acids 70, aldehydes, and isocyanides in an Ugi-3CR in TFE at 40 °C (Scheme [17]). The authors prepared 27 examples of γ-lactams 71 by utilizing this methodology, including the successful syntheses of piracetam (72a) (58%), etiracetam (72c) (53%), nefiracetam (72d) (39%) and pramiracetam (72e) (quantitative yield).

Scheme 17 Synthesis of γ-lactams 71 and 72a,c–e

Cotinine (73), a predominant metabolite of nicotine (74), is an important γ-lactam with a wide range of pharmacological properties.[54] Inspired by its diverse medicinal properties, in 2015, Vazquez and co-workers[55] developed a two-step Ugi-4CR/post-condensation strategy for the synthesis of highly substituted cotinine and iso-cotinine analogues 80 (Scheme [18]). First, an InCl₃-catalyzed multicomponent reaction was performed between 3-chloropropionic acid (75), 3-pyridine aldehyde, amines, and isocyanides to afford Ugi adducts 76, which subsequently gave γ-lactams 80 in moderate to excellent yields via t-BuOK-mediated cyclization under MW heating conditions. However, when pyridine-2(4)-carboxaldehydes were used, lactams 80 were obtained directly without the use of a base at a slightly elevated temperature. It was claimed that the slightly basic nature of the reaction medium due to the presence of a primary amine and a pyridine moiety facilitates anion generation by abstracting a highly acidic peptidyl proton adjacent to the 2- or 4-pyridinecarboxaldehyde, followed by intramolecular cyclization to give the final products in one step. The mechanism proposed by the authors suggests that the intramolecular cyclization might proceed via two routes (Scheme [18]).[55] Either a base-mediated S_N2 process via intermediate 79 to give the cyclized product (route A), or in situ formation of Michael acceptor 78 from intermediate 77 followed by nucleophilic addition to generate the cyclic product 80 (route B). However, according to Baldwin’s rules, the 5-endo-trig cyclization of intermediate 78 is disfavored and thus the reaction is less likely to follow route B.

Scheme 18 Synthesis of highly substituted γ-lactams 80

In a parallel investigation, the synthesis of indole-linked γ-lactams 80 [where Ar = 2-(1H-indole)] via a two-step Ugi-4CR followed by a K₂CO₃-mediated S_N2 cyclization in DMF at 100 °C was reported by Shiri and co-workers.[56]

In 2012, Hulme and co-workers[57] developed a one-pot, two-step methodology for the synthesis of 1,5-disubstituted-tetrazole-linked γ-lactams 82 by reacting keto-ester methyl levulinate 81 with isocyanides, TMSN₃ and a wide range of primary amines via an Ugi-4CR to afford Ugi adducts, which were subsequently cyclized under acidic conditions to give the final cyclized products 82 in poor to excellent yields (Scheme [19]). A large library of γ-lactam products 82 was prepared by using a 96-well plate production method.

Scheme 19 Synthesis of 1,5-disubstituted-tetrazole-linked γ-lactams 82

Solid-phase organic synthesis is a powerful synthetic tool that is used widely in the synthesis of complex bioactive molecules.[58] In 2010, Liu and Nefzi[59] reported the synthesis of enantiopure N-substituted γ-lactams 86 via solid-phase synthesis (Scheme [20]). Bifunctional polymer-supported glutamic acid 83 was reacted with cyclohexanone or Boc-piperidone 84 and an isocyanide via an Ugi-3CR under heating conditions to generate resin-supported Ugi adducts 85, which upon cleavage of the solid support gave enantiopure γ-lactams 87 in excellent yields. Further, in order to increase the complexity and diversity, the authors synthesized N-substituted γ-lactam analogues 86. First, deprotection of Ugi adducts 85 was carried out followed by amidation using various carboxylic acids, sulfonyl chlorides, isocyanates, or thioisocyanates. Finally, cleavage of the resin gave γ-lactams 86 in excellent yields.

Scheme 20 Synthesis of enantiopure γ-lactams 87 and N-substituted γ-lactams 86 via solid-phase synthesis

El Kaïm and co-workers[60] have developed a two-step process for the synthesis of γ-lactams 91 using an Ugi-4CR followed by a radical cyclization (Scheme [21]). In this transformation, initially allylamine (88), chloroacetic acid (89), aldehydes, and isocyanides were reacted together to form an Ugi adduct. This was followed by the addition of KS₂COEt resulting in the generation of Ugi-xanthate adducts 90 in good yields after 1 hour at room temperature. Adducts 90 were readily converted into the expected γ-lactam products 91 as 1:1 mixtures of separable diastereoisomers via 5-exo-trig cyclization by heating under radical cyclization conditions in the presence of 15 mol% of dilauroyl peroxide (DLP) as a radical initiator.

Scheme 21 Synthesis of γ-lactams 91 using an Ugi-4CR followed by radical cyclization

Later, in 2010, El Kaïm and colleagues extended the scope of the above-mentioned reaction by using propargyl amine (92), instead of allylamine (88), and stoichiometric amounts of DLP to obtain β-methylene γ-lactams 94 from adducts 93 under slightly modified Ugi-4CR/reductive radical cyclization conditions (Scheme [22]).[61]

Scheme 22 Synthesis of β-methylene γ-lactams 94

A two-step synthesis of enamide γ-lactams 97 via an Ugi-4CR followed by a base-mediated propargylation reaction has also been reported (Scheme [23]).[62] First, Ugi adducts 95 were prepared in good to excellent yields (67–95%) via Ugi-4CRs of aldehydes, amines, isocyanides, and carboxylic acids. Next, the adducts 95 underwent alkylation mediated by NaH (2.5 equiv) with propargyl bromide (96) in the presence of TBAF followed by formation of enamide γ-lactams 97 through cyclization of an amide with an alkyne. It was noted that TBAF played an important role as an additive in the formation of cyclic products 97 and lower equivalents of NaH (1 equiv) resulted in the formation of alkylated product 98 (51%) along with the recovery of unreacted Ugi adduct 95 (32%).

Scheme 23 Synthesis of enamide γ-lactams 97

Dömling and co-workers[63] developed a fast and efficient methodology for the synthesis of 1,5-disubstituted tetrazolo γ- and δ-lactams 102 in moderate to excellent yields via Ugi–azide reactions followed by a deprotection and cyclization strategy (Scheme [24]). Adduct 101 was readily prepared by treatment of trityl amine (99) with aliphatic aldehyde 100, an isocyanide and TMSN₃ at 100 °C under MW irradiation. The adduct 101 was further converted into lactam 102 by trityl group deprotection followed by base-mediated cyclization. It was noted that due to the steric hindrance generated by the trityl moiety, the Ugi reactions only proceeded under MW heating and only aliphatic aldehydes were well tolerated. Additionally, protein data bank analysis of these γ- and δ-lactams revealed the presence of strong tri-directional H-bond donor–acceptor interactions with the amino acids of the binding sites.

Scheme 24 Synthesis of unsubstituted tetrazolo γ- and δ-lactams 102 via Ugi–azide reactions

Recently, Polindara-García and co-workers developed[64] an efficient microwave-assisted two-step method for the synthesis of highly substituted γ-lactams 107 via an Ugi-4CR followed by a radical cyclization–oxyamination process promoted by ammonium persulfate and TEMPO (106) (Scheme [25]). First, the Ugi-4CR was performed utilizing acid 103, aldehyde 104, an amine, and an isocyanide in the presence of InCl₃ (2 mol%) in a MW at 70 °C to afford 1,3-dicarbonyl Ugi adducts 105 in excellent yields. Next, as a result of thermal homolytic cleavage an anion radical species 108 was generated from (NH₄)S₂O₈, which upon single-electron transfer (SET) with Ugi adduct 105 gave radical 110 and ammonium hydrogen sulfate (109). Subsequently, radical 110 was readily converted into cyclized radical 111 via intramolecular 5-exo-trig cyclization onto the alkene. Finally, radical–radical coupling between 111 and TEMPO (106) resulted in the formation of the final γ-lactam 107. All the isolated products were obtained in moderate to poor (82:18 to 49:51) diastereomeric ratios.

Scheme 25 Synthesis of highly substituted γ-lactams 107

In 2012, Khan and Saxena[65] published the synthesis of a series of lactams 114 in moderate to excellent yields via a one-pot Parikh–Doering oxidation/dehydration/Ugi cyclization (Scheme [26]). The reaction employed N-formylated aminols 112, which underwent oxidation to yield intermediates 113. Dehydration followed by condensation with an amine and an acid through an Ugi-3CR resulted in the formation of cyclized lactams 114. The authors reported 21 examples using this strategy, including the syntheses of five- to eight-membered lactams.

Scheme 26 Synthesis of a series of lactams 114

2.3.2

Benzo-Fused γ-Lactams

In 2006, Zhu and co-workers[66] reported the synthesis of benzo-fused γ-lactams 116 via a two-step process involving an Ugi-4CR followed by a palladium-catalyzed intramolecular Buchwald–Hartwig reaction (Scheme [27]). Initially the functionalized ortho-substituted iodobenzaldehydes 115 were reacted with amines, carboxylic acids, and isocyanides in MeOH at room temperature to give Ugi products in 21–99% yield. These Ugi adducts were subsequently treated in the presence of Pd(dba)₂ as the catalyst and MePhos as the ligand at 100 °C under microwave heating conditions to obtain the final cyclized products 116 in high yields. It was noted that microwave heating not only accelerated the reaction rate but also improved the efficiency of the intramolecular Buchwald–Hartwig coupling reaction. The advantage of this method is that a variety of functional groups such as esters, amines, and ethers, and heterocycles such as pyridine and indole were well tolerated. Additionally, in 2009, Zhu and colleagues[67] reported Ugi-4CRs followed by Pd-catalyzed intramolecular α-CH arylation of amides to give benzo-fused γ-lactams 118 in moderate to excellent yields, which are structural analogues of γ-lactams 116. The authors treated ortho-halo-substituted anilines 117 with an aldehyde, a carboxylic acid, and an isocyanide to form Ugi adducts, which then underwent intramolecular cyclization using BINAP as the ligand under otherwise previously reported identical conditions to yield the final products 118 (Scheme [27]).

Scheme 27 Synthesis of benzo fused γ-lactams 116 and 118 via Ugi-4CR/palladium-catalyzed intramolecular Buchwald–Hartwig reactions

Methyl 2-formylbenzoate (119) is an important bifunctional starting material. Chen and co-workers[68] reported the synthesis of three types of benzo-fused γ-lactam analogues, 120, 122, and 124, by using common aldehyde 119 in an Ugi-MCR followed by intramolecular amidation (Scheme [28]). Initially the Ugi-3CR between aldehyde 119, an isocyanide, and an amine was carried out in the presence of catalytic phenylphosphonic acid to afford Ugi adducts, which then underwent intramolecular cyclization under acidic conditions at 120 °C in a MW to generate benzo-fused γ-lactams 120. The synthesis of 122 was achieved by performing an Ugi-4CR utilizing amine 121 followed by cyclization via removal of the 2,4-dimethoxybenzyl group under microwave irradiation and acidic conditions. Similarly, benzimidazole-linked benzo-fused γ-lactam 124 analogues were prepared via Ugi-3CRs using Boc-protected isocyanide 123 to yield intermediate 125 via the Ugi product and Boc deprotection followed by amidation under acidic conditions. It is important to note that all the analogues were prepared in one-pot processes.

Scheme 28 Synthesis of benzo-fused γ-lactam analogues 120, 122, and 124

Dithiocarbonates or xanthates are widely used in organic synthesis due to their unique ability to store reactive radicals in a dormant form.[69a] In 2014, Gámez-Montaño’s research group[69b] employed p-anisidine (126), chloroacetic acid, aldehydes and isocyanides followed by potassium ethyl xanthogenate (KS₂COEt) to prepare xanthates 127 via a one-pot InCl₃-catalyzed Ugi-4CR followed by an S_N2 process. The xanthates then undergo free-radical cyclization to afford the final benzo-fused γ-lactams 128 by using dilauroyl peroxide (DLP) as a free-radical initiator and oxidant. DFT-based calculations were performed to support the kinetics and thermodynamics of the xanthate-mediated free-radical cyclization (Scheme [29]).

Scheme 29 Synthesis of benzo-fused γ-lactams 128 via free-radical cyclization

In 2006, highly substituted benzo-fused γ-lactams 131 were synthesized in moderate to good yields via a one-pot Ugi-4CR/Heck reaction (Scheme [30]).[70] The 2-bromoanilines 129 underwent an Ugi-4CR with aldehydes, isocyanides, and a variety of acrylic acids 130 to give the corresponding Ugi adducts. Heating these adducts in the presence of Pd(OAc)₂ (3 mol%) and PPh₃ (6 mol%) afforded benzo-fused γ-lactams 131 as isomeric mixtures through an intramolecular Heck cyclization.

Scheme 30 Synthesis of highly substituted benzo-fused γ-lactams 131

In 2011, Balalaie and co-workers[71] described an efficient palladium-catalyzed Ugi-carbopalladative cyclization–Buchwald methodology for the synthesis of benzo-fused γ-lactams 137 (Scheme [31]). Treatment of 2-iodoaniline (132) with phenylpropiolic acid (134), aldehydes and isocyanides gave Ugi adducts through an Ugi-4CR. The formed Ugi adducts then underwent a domino carbopalladative cyclization–Buchwald reaction initiated by the addition of cyclic secondary amines 136 in the presence of Pd(OAc)₂ as the catalyst and tri(2-furyl)phosphine (135) as the ligand in toluene under reflux conditions to afford benzo-fused γ-lactams 137 in excellent yields (63–85%). It was noted that all the products formed with Z-configuration of the double bond, as confirmed by NMR studies.

Scheme 31 Synthesis of benzo-fused γ-lactams 137

The tetrazole moiety is found in various bioactive and pharmaceutically important molecules.[72] In 2008, Marcaccini et al.[73] reported the synthesis of 1,5-disubstituted-tetrazole-linked benzo-fused γ-lactams 140 via an Ugi-4CR followed by cyclization (Scheme [32]). It was claimed that the reaction can proceed via two routes based on the nature of the amine source used. When anilines were used as the amine source, the reaction follows route A, where initially the Ugi adducts 139 (73–83%) were formed, and subsequent base-mediated cyclization resulted in the formation of benzo-fused γ-lactams 140 in excellent yields. On the other hand, when alkyl and benzylic amines were used, the reaction proceeded through route B to give directly the final cyclized products 140 without any base in a one-pot manner. Later, in 2013, Hulme’s research group[74] reported the synthesis of similar benzo-fused γ-lactam analogues 140 in moderate to good yields under the conventional Ugi–azide reaction conditions at room temperature (Scheme [32]). Also, these authors synthesized an additional 96 analogues using a 24-well plate method, however, in the majority of cases, poor yields were obtained.

Scheme 32 Synthesis of 1,5-disubstituted-tetrazole-linked benzo-fused γ-lactams 140

In 2006, Gámez-Montaño and co-workers[75] reported the synthesis of 1,5-disubstituted-tetrazole-linked benzo-fused γ-lactams 144 in 12–76% yields under mild conditions via a one-pot Ugi-azide/(N-acylation/exo-Diels–Alder)/aromatization–dehydration strategy (Scheme [33]). The Ugi-tetrazole adducts 142 were synthesized by reacting furan-2-ylmethanamine (141), aldehydes, isocyanides, and TMSN₃ in MeOH, which on reaction with maleic anhydride (143) in toluene underwent N-acylation to give intermediates 145. The acid intermediates 145 were readily converted into cycloadducts 146 via an intramolecular Diels–Alder reaction. For the formation of the final aromatized products 144, PTSA (3 equiv) was used under MW heating conditions in dry toluene. The sequential mechanism proposed by the authors was supported by DFT calculations.

Scheme 33 Synthesis of 1,5-disubstituted-tetrazole-linked benzo-fused γ-lactams 144

Zhu and co-workers,[76] in 2008, reported the synthesis of benzoxazole-linked benzo-fused γ-lactams 152 via a three-step Ugi-4CR followed by regiospecific sequential intramolecular Cu-catalyzed O-arylation and Pd-catalyzed C-arylation (Scheme [34]). Treatment of 2-iodobenzoic acid (147) with isocyanide 148 along with different aldehydes and amines resulted in the formation of Ugi adducts 149, which underwent intramolecular O-cyclization in the presence of CuI (5 mol%) and thiophene-2-carboxylic acid (150) under heating conditions to give benzoxazole intermediates 151 in poor to quantitative yields. The resulting intermediates 151 were readily converted into products 152 via Pd-catalyzed C-arylation.

Scheme 34 Synthesis of benzoxazole-linked benzo-fused γ-lactams 152

Scheme 35 DOS of polycyclic benzo-fused γ-lactams 161 and 162

Scheme 36 DOS of spirocyclic γ-lactam 166 and α,β-unsaturated γ-lactam oxindoles 167

In 2015, a diversity-oriented synthesis (DOS) approach towards polycyclic benzo-fused γ-lactams 161 and 162 was carried out via palladium-catalyzed C–C bond formation as the key step (Scheme [35]).[77] Initially benzoyloxyacetaldehyde 153, 2-iodobenzoic acid 154, and isocyanides were reacted with allyl/homoallyl amines 155 or benzylamine/heteroaromatic methenamines 158 via a Ugi-4CR. This was followed by base-mediated elimination of the benzoate group to give dehydroalanine adducts 156 and 159. The adduct 156 underwent a Pd-catalyzed double 5-exo-trig/Heck cascade cyclization when the amine input was allylamine or a 5-exo-trig/6-exo-trig Heck reaction in the case of a homoallyl amine to give tricyclic benzo-fused γ-lactams 162. With benzylamines, 5-exo/C–H insertion took place to afford the tetracyclic benzo-fused γ-lactams 161. The reaction might follow a conventional intramolecular Heck reaction pathway. Initially, oxidative addition occurs followed by intramolecular alkene insertion to generate Pd complexes 157 and 160. Next, complex 157 undergoes a second intramolecular alkene insertion and β-hydride elimination to afford the final cyclized product 162. On the other hand, complex 160 undergoes C–H oxidative insertion to give product 161.

2.3.3

Spiro-γ-Lactams

In 2018, Andreana and Maddirala[78] developed an efficient DOS of spirocyclic γ-lactams 166 and α,β-unsaturated γ-lactam oxindoles 167 in good to excellent yields via a one-pot, three-step post-Ugi domino transformation/cyclization strategy (Scheme [36]). This three-step sequential strategy started with an Ugi-4CR followed by an acid-promoted intramolecular transamidation and finally a base-mediated cyclization to give spirocyclic γ-lactams 166 and α,β-unsaturated γ-lactam oxindoles 167. The acid-mediated Boc deprotection of Ugi intermediate 163 resulted in the generation of aniline intermediate 164, which subsequently cyclized through an intramolecular transamidation process to yield compound 165 and methylamine as a byproduct. Next, compound 165 underwent a K₂CO₃-mediated intramolecular cyclization via an S_N2 process to afford target compounds 166 when the acid component was 1-chloropropionic acid and compounds 167, via 5-endo-dig cyclization, when propiolic acid was used.

Scheme 37 Synthesis of functionalized spirocyclic γ-lactam scaffolds 171

In 2015, the group of Ghandi published an efficient one-pot strategy for the synthesis of functionalized spirocyclic γ-lactam scaffolds 171 via an Ugi-4CR followed by two consecutive post-condensation intramolecular C–C and N–C cyclizations, respectively (Scheme [37]).[79] The developed strategy utilizes electron-deficient substituted 2-chloroquinoline-3-carbaldehydes 168, amines, 2-chloronicotinic acid or 2-bromobenzoic acid 169 and isocyanides to generate in situ an Ugi product 170 containing four reactive sites. Further, adduct 170 undergoes two bis-annulation post-Ugi processes in the presence of the base Cs₂CO₃ (2 equiv) to give the final spirocyclic γ-lactams 171 in excellent yields. The structures of the synthesized products were confirmed by single-crystal X-ray-diffraction analysis.

Stolyarenko and co-workers[80] reported the synthesis of 1,5-disubstituted-tetrazole-linked spirocyclic γ-lactams 173 via a one-pot, two-step Ugi–azide MCR process (Scheme [38]). The authors effectively utilized bifunctional γ-oxo ester reagents 172 with several amines, isocyanides and TMSN₃ to obtain the Ugi adducts, which were further reacted under acidic conditions to give the final products 173 in moderate to good yields (50–72%). The products 173 were characterized by X-ray analysis.

Scheme 38 Synthesis of 1,5-disubstituted-tetrazole-linked spirocyclic γ-lactams 173

Scheme 39 Synthesis of spirocyclic γ-lactam cyclohexadienones 175

Andreana and Santra reported the synthesis of spirocyclic γ-lactam cyclohexadienones 175 via an Ugi-4CR followed by a 5-exo-trig Michael cyclization using water as the solvent under microwave irradiation (300 W) at 200 °C (Scheme [39]).[25] It is important to note that the highly complex spirocyclic γ-lactam products 175 were synthesized in excellent yields by using bifunctional carboxylic acid 174 as the substrate without using any additive. Also, it was noted that transition state stabilization by H₂O, the sterics of the carboxylic acid substrate, and the presence of an electron-donating group on the amine influenced the formation of spirocyclic-γ lactam scaffolds 175 with the help of MW heating.

Another outstanding example of the synthesis of spirocyclic γ-lactam cyclohexadienones 178 was described by Gámez-Montaño and colleagues[81] via a two-step Ugi-4CR followed by microwave-assisted radical cyclization (Scheme [40]). Reaction of benzylamine 176, an aldehyde, chloroacetic acid, and an isocyanide followed by addition of the potassium salt of xanthic acid (KS₂COEt) resulted in the generation of Ugi xanthate adduct 177. Next, microwave-assisted radical spirocyclization was performed to yield spirocyclic γ-lactam 178 in the presence of DLP as a radical initiator at 100 °C. It was noted that, inseparable diastereomeric mixtures (1:1 to 7:3) were obtained for the products where R¹ ≠ R².

Scheme 40 Synthesis of spirocyclic γ-lactam cyclohexadienones 178

Scheme 41 A two-step synthesis of 1,5-disubstituted-linked spirocyclic γ-lactams 181

Scheme 42 Synthesis of spirocyclic α,β-unsaturated γ-lactam intermediate 185

Later, in 2017, the same research group[82] synthesized 1,5-disubstituted linked spirocyclic γ-lactam oxindoles 181 via two experimental steps: (a) a one-pot Ugi–azide/Pictet–Spengler process coupled with (b) a one-pot oxidative spiro-rearrangement (Scheme [41]). Initially, different isocyanides were reacted with tryptamine (179), formaldehyde, and TMSN₃ under heating conditions to afford bis- heterocyclic Ugi products 180, which were further subjected to oxidative spiro-rearrangement in the presence of NBS under acidic conditions to give the spirocyclic-γ-lactam oxindoles 181. It was noted that except for the benzyl isocyanide analogue, all the other products were formed in excellent yields. Cleavage of the benzylic group under oxidative conditions led to a lower yield of the benzyl isocyanide analogue (70%).

Due to their versatility and flexibility, MCRs are important in numerous areas of chemistry including the total synthesis of natural products.[83] An efficient example of the synthesis of the natural product 186 containing an α,β-unsaturated γ-lactam core by the effective use of a convertible isocyanide-based Ugi reaction as the key step was disclosed by Sarpong and co-workers in 2012.[84] Convertible isocyanides are a class of isocyanides that can be transformed into various functionalities once the condensation product has been formed.[85] As a result, the use of convertible isocyanides in natural product synthesis has increased. Sarpong reported the synthesis of fused polycyclic α,β-unsaturated γ-lactam 186, a base core found in the Kopsia alkaloids lapidilectine B, grandilodine C, and tenuisine A, from spirocyclic α,β-unsaturated γ-lactam intermediate 185, itself obtained via an Ugi-4CR (Scheme [42]). The Ugi-4CR between tryptamine (179), cyclohexanone 182, convertible isocyanide 183, and acetic acid in MeOH resulted in the formation of Ugi adduct 184 in 95% yield. Subsequent esterification, Dieckmann condensation, NaBH₄ reduction and intramolecular elimination afforded key intermediate 185 in an overall yield of 85%.

Another elegant example of the efficient use of a convertible isocyanide-based Ugi reaction in the synthesis of the natural product TAN1251C (191) was published by Kan and co-workers (Scheme [43]).[86] Initially, an Ugi-4CR between cyclohexanone 182, amine 187, N-protected amino acid 188 and 2-bromo-6-pyridine isocyanide (189) resulted in the formation of the corresponding Ugi adduct in 75% yield, which upon sodium methoxide mediated Dieckmann condensation at 50 °C followed by addition of triflic imidate in the presence of excess KHMDS afforded key spirocyclic α,β-unsaturated γ-lactam triflate intermediate 190 in 48% overall yield. Next, key intermediate 190 was readily converted into the desired natural product TAN1251C (191) after performing several multistep reactions.

Scheme 43 Synthesis of spirocyclic α,β-unsaturated γ-lactam triflate 190

2.3.4

α,β-Unsaturated γ-Lactams

The combination of an Ugi-4CR and ring-closing metathesis was described by Keum and colleagues (Scheme [44]).[87] Here, adducts 194 were formed in good yields after Ugi-4CRs between acrylic acid (192), allylamine (193), aldehydes, and isocyanides at 0 °C to room temperature. Subsequently, ruthenium-catalyzed ring-closing olefin metathesis resulted in the formation of α,β-unsaturated γ-lactams 195. Optimization studies revealed that 5 mol% of the Grubbs catalyst in either toluene or benzene was sufficient for the metathesis reaction to give the expected cyclized products 195. When propargylamine was used, vinyl-substituted γ-lactam 196 was obtained in 64% yield via a two-step Ugi-4CR/enyne metathesis reaction.

Scheme 44 Synthesis of α,β-unsaturated γ-lactams 195

A small series of α,β-unsaturated γ-lactams 198 was synthesized by the group of El Kaïm[88] via an Ugi-4CR followed by base-mediated intramolecular cyclization in a one-pot manner (Scheme [45]). The formation of the product was highly dependent on the acidity of the peptidyl tertiary proton of the Ugi intermediate 197. Substituted aromatic or heteroaromatic aldehydes offered sufficiently acidic peptidyl protons and hence were well tolerated in the reaction, in contrast to butyraldehyde which failed to give the cyclized product even after prolonged heating.

In 2014, Van der Eycken and co-workers[89] disclosed the synthesis of α,β-unsaturated γ-lactams 201 via a one-pot Ugi-4CR followed by 5-endo-dig carbocyclization and retro-Claisen fragmentation at 80 °C (Scheme [46]). The authors used 3-substituted propiolic acids and phenyl glyoxals along with different amines and isocyanides to give Ugi adducts 199. Further, the intermediates 199 spontaneously underwent a 5-endo-dig carbocyclization to afford γ-lactams 200, which were subsequently converted into the final α,β-unsaturated γ-lactams 201 via retro-Claisen fragmentation through cleavage of the benzoyl moiety. The presence of an additional electron-withdrawing (carbonyl) group next to the enolizable tertiary carbon and the Michael acceptor nature of a triple bond conjugated with an amide triggered the 5-endo-dig carbocyclization to give intermediate 200. The authors demonstrated the importance of the electron-withdrawing carbonyl group by replacing the phenyl glyoxal with paraformaldehyde, the reaction of which gave only the acyclic Ugi adduct without the formation of the desired cyclized final product.

Scheme 45 Synthesis of α,β-unsaturated γ-lactams 198

Scheme 46 Synthesis of α,β-unsaturated γ-lactams 201 via a one-pot Ugi-4CR/5-endo-dig carbocyclization/retro-Claisen fragmentation strategy

Later, in 2016, the same research group demonstrated the synthesis of highly substituted α,β-unsaturated γ-lactams 205 via a domino Ugi-4CR/Michael process starting from nitrogen-containing heterocyclic aldehydes 202, amines, 2-alkynoic acids and isocyanides (Scheme [47]).[90] Initially the Ugi adduct 203 formed with the nitrogen heterocycle acting as a base to generate carbanion 204. This intermediate then underwent a Michael addition to afford the final product 205. A lower yield (32%) was observed with 6-bromopicolinaldehyde, even after heating at 50 °C. The authors used this protocol to synthesize a variety of substituted α,β-unsaturated γ-lactams in a one-pot manner.

Scheme 47 Synthesis of highly substituted α,β-unsaturated γ-lactams 205

In 2016, Srivastava and co-workers[91] prepared a series of alkaloid-like tricyclic α,β-unsaturated γ-lactams 208 via a one-pot Ugi-4CR, acid-mediated ipso-cyclization and an aza-Michael addition (Scheme [48]). The authors utilized a variety of substituted 4-methoxyanilines 206 as amine substrates, aldehydes or ketones, propiolic acids 207 and tert-butyl isocyanide to afford Ugi-adducts 209. These adducts underwent acid-catalyzed intramolecular ipso-cyclization in a 5-endo-dig manner to generate spirocyclic α,β-unsaturated γ-lactam intermediates 210. Cleavage of the tert-butyl group with excess H₂SO₄ then afforded acetamides 211 that yielded the tricyclic α,β-unsaturated γ-lactam products 208 via an intramolecular aza-Michael addition proceeding through a 6-exo-trig route. It was noted that when cyclohexyl isocyanide was used, only spirocyclic intermediate 210 was isolated from the respective Ugi adduct after sulfuric acid treatment. Thus, the presence of a tert-butyl group was crucial, which after cleavage triggered the aza-Michael addition to give the final products.

Scheme 48 Synthesis of alkaloid-like tricyclic α,β-unsaturated γ-lactams 208

In 2016, Van der Eycken and co-workers[92] developed an efficient two-step diversity-oriented synthetic strategy for the synthesis of fused tris-heterocyclic α,β-unsaturated γ-lactams 216 via a domino Ugi-4CR followed by a Michael addition reaction (Scheme [49]). The disclosed methodology utilizes imidazole-2-carbaldehyde (212), propargyl amines 213, 2-alkynoic acids 214, and isocyanides to afford imidazo-linked α,β-unsaturated γ-lactams 215 through an Ugi-4CR/Michael addition in one-pot. Further, the AgSbF₆ (5 mol%) catalyzed intramolecular heteroannulation of intermediate 215 under aqueous conditions led to the synthesis of final products 216 in moderate to excellent yields. The authors offered 21 examples of this methodology, including the preparation of compounds 216a and 216b in which dimethyl- and cyclohexyl-substituted propargylamines were used, respectively. Furthermore, it was also claimed that this methodology could be performed in a one-pot, three-step fashion to furnish the final product 216 in an overall yield of 26%.

Scheme 49 Synthesis of fused tris-heterocyclic α,β-unsaturated γ-lactams 216

2.3.5

Fused-Polycyclic γ-Lactams

McCluskey and co-workers[93] reported the Ugi-4CR between an alkenoic acid, 2-furaldehyde (217), isocyanides, and amines in MeOH to afford acetylenic furan intermediates 218, which upon heating at 200 °C in a sealed tube underwent an intramolecular Diels–Alder reaction to give fused tricyclic γ-lactams 219 in moderate to good yields (Scheme [50]). It was noted that lower yields were obtained when N,N-dimethylaminopropylamine was used due to proton scavenging of the acid by a tertiary amine group. In this case, the addition of 2 equivalents of the alkenoic acid resulted in formation of the final tricyclic product 219 in 72% yield. A disadvantage of this protocol was the requirement of an extremely high temperature (200 °C) for a longer time period (36 h).

Scheme 50 Synthesis of fused tricyclic γ-lactams 219

Santra and Andreana[94] reported the synthesis of natural-product-like fused polycyclic bis-lactams 222 by using an Ugi-4CR/Michael/aza-Michael cascade reaction in a one-pot manner (Scheme [51]). It was noted that the bulky nature of the R¹ substituent on the carboxylic acid 221 and R³ on the isocyanide substrate played an important role in the formation of products 222, 223, and 224. A less bulky group (NHMe) at R¹ led to the synthesis of fused tricyclic γ-lactam 223 through a 6-exo-trig aza-Michael route. However, the presence of bulky R³ substituents led to a 5-exo-trig aza-Michael path being followed as a result of the proximity effect instead of a 6-exo-trig aza-Michael addition, thus ultimately giving rise to fused tricyclic bis-γ-lactam 222 and fused tetracyclic bis-γ-lactam 224 products.

Scheme 51 Synthesis of natural-product-like fused polycyclic bis-lactams 222

Scheme 52 Synthesis of natural-product-like fused tricyclic bis-γ-lactams 230

In 2006, Ivachtchenko and co-workers[95] demonstrated the synthesis of diastereomerically pure natural-product-like fused tricyclic bis-γ-lactams 230 via an Ugi-4CR/intramolecular Diels–Alder (IMDA) sequence followed by an unexpected acid-mediated rearrangement (Scheme [52]). Initially, 5-methylfuran-2-carbaldehyde (225), maleic acid monoamides 226, amines, and isocyanides were reacted together under heating to give bicyclic bridged adduct 228 fused with a newly formed γ-lactam ring (A) from Ugi intermediate 227 via a one-step Ugi-4CR/IMDA sequence. The acid-mediated rearrangement mechanism proposed by the authors began with heterolytic cleavage of the C1–C2 bond in the intermediate 228 assisted by the secondary amide side chain, leading to the generation of transient intermediate 228A with another γ-lactam ring (B) and a hydrolytically prone cyclic enol ether moiety. Subsequent acid-promoted opening of the cyclic enol ether of 228A led to the generation of carbocation 228B, which was followed by carbocation trapping by the amide carbonyl side chain and hydrolysis resulting in the formation of tricyclic fused bis-γ-lactam product 230 with loss of the R³-NH₂ group (Scheme [52]). It was also claimed that treatment of the Ugi-4CR/IMDA product 228 with a catalytic amount of the Lewis acid BF₃·Et₂O in a nonpolar medium resulted in the formation of fused-benzo-γ-lactam 231 in 75% yield via aromatization and with no rearrangement product being detected.

Van der Eycken and co-workers[96] reported the synthesis of fused tetracyclic γ-lactams 233 via an Ugi-4CR followed by a gold-catalyzed cyclization in a two-step process (Scheme [53]). First, they reacted 3-formylindoles 232 and propargylamine with a variety of carboxylic acids and isocyanides to give Ugi products 234 in moderate to excellent yields (58–89%). Adducts 234 were then subjected to an Au(PPh₃)SbF₆ (5 mol%) catalyzed domino cyclization to furnish the products 233 in moderate to excellent yields. The Au-catalyzed cyclization mechanism proposed by the authors began with intramolecular frontal exo-dig attack of the indole core on the terminal alkyne (intermediate 235), which was activated by cationic Au-coordination. This was followed by amidic NH trapping of the iminium ion (intermediate 236) and protodeauration resulted in the formation of product 233 with S stereochemistry at two of the newly formed stereocenters.

Scheme 53 Synthesis of fused tetracyclic γ-lactams 233 via an Ugi-4CR/gold-catalyzed cyclization

2.4

δ-Lactams

In 2010, Deprez and co-workers[50] reported the synthesis of δ-lactams 238 by using bifunctional 5-ketohexanoic acid (237), amines, and isocyanides via an Ugi-3CR under solvent-free microwave heating conditions at 100 °C (Scheme [54]). It was noted that this methodology gave higher yields of δ-lactams in shorter reaction times compared to the previously published lengthy conventional methods,[48] [51] where the key Mumm rearrangement step occurs via a less favorable seven-membered cyclic transition state, thus resulting in lower yields.

Scheme 54 Synthesis of δ-lactams 238

In 2012, Hulme and co-workers[97] synthesized two series of 1,5-disubstituted tetrazole-linked δ- and ε-lactams 240 via a one-pot Ugi–azide reaction followed by intramolecular amide formation (Scheme [55]). For the synthesis of δ-lactams, 5-oxohexanoic acid 239 (R¹ = OH, n = 1) was reacted with amines, isocyanides, and TMSN₃ in MeOH at room temperature. A subsequent 1,1′-carbonyldiimidazole (CDI) mediated intramolecular amidation in THF then gave the δ-lactam products in moderate yields (conditions a). On the other hand, ε-lactams were obtained by reacting methyl 6-oxoheptanoate 239 (R¹ = OMe, n = 2), amines, isocyanides, and TMSN₃ under conventional Ugi–azide reaction conditions to give the expected Ugi adducts, which upon base-mediated hydrolysis followed by SOCl₂ activation were readily converted into seven-membered cyclic ε-lactams after 12 hours at reflux (conditions b).

Scheme 55 Synthesis of 1,5-disubstituted tetrazole-linked δ- and ε-lactams 240

In 2004, Akritopoulou-Zanze and co-workers[98] synthesized isoxazole-fused δ-lactams 243 in good yields via a two-step Ugi-4CR/intramolecular nitrile oxide cycloaddition reaction (Scheme [56]). First, the Ugi adducts 242 were synthesized by reacting nitro-substituted carboxylic acid 241, propargylamine, aldehydes, and isocyanides in methanol, which upon treatment with POCl₃ in the presence of Et₃N afforded products 243 via an intramolecular [3+2] nitrile oxide cycloaddition. When allylamine was used instead of propargylamine under similar reaction conditions, isoxazoline-fused δ-lactam 244 was obtained in 47% yield. It was reported that the use of excess POCl₃ and Et₃N resulted in the decomposition of the product, thus giving lower yields.

Scheme 56 Synthesis of isoxazole-fused δ-lactams 243

Gracias and co-workers[99] have synthesized benzo-fused δ-lactams 247 in quantitative yields via an Ugi-4CR followed by a microwave-assisted intramolecular Heck reaction (Scheme [57]). This two-step sequential protocol started with the reaction between 2-bromobenzaldehyde, cyclic or acyclic α,β-unsaturated carboxylic acids 245, benzylamine and benzyl isocyanide to give Ugi adducts 246 in excellent yields. Next, adducts 246 underwent a Pd-catalyzed intramolecular Heck cyclization under microwave heating at 125 °C to generate the cyclized products 247 in excellent yields (91–97%). The use of cyclic α,β-unsaturated carboxylic acids led to the formation of spirocyclic benzo-fused δ-lactams 247b and 247c with excellent stereoselectivities. It was noted that the reaction times for the Heck cyclization were greatly reduced and increased yields of the cyclized products were obtained under microwave heating conditions.

Scheme 57 Synthesis of benzo-fused δ-lactams 247

Scheme 58 Synthesis of spirocyclopenta-fused and cyclopenta-fused δ-lactams 250

In 2013, Van der Eycken and co-workers[100] reported an efficient synthesis of spirocyclopenta-fused and cyclopenta-fused δ-lactams 250 via a two-step Ugi-4CR followed by gold-catalyzed regioselective tandem cyclization through Csp³–H functionalization (Scheme [58]). A multicomponent reaction between propargylamine, alkynoic acid 248, aldehydes, and isocyanides gave Ugi adducts 249 in excellent yields. Adducts 249 were then subjected to an intramolecular gold-catalyzed tandem cyclization under heating conditions to afford the cyclized products 250 in 52–91% yields. A plausible reaction mechanism was proposed in which the first step is the formation of a gold acetylide π-activated butynamide intermediate 251. Subsequent catalytic transfer followed by a 6-endo-dig cyclization leads to the gold vinylidene intermediate 252. Next, this highly reactive species may undergo C–H insertion and protodeauration to give the final product 250.

Scheme 59 Synthesis of bridged bicyclic δ-lactams and ε-lactams 253

Scheme 60 Synthesis of polycyclic fused δ-lactams 258, 259 and 261

In 2007, Judd and co-workers[101] synthesized a small library of bridged bicyclic six- and seven-membered lactams 253, with high (up to 98:2) diastereoselectivity, via a three-step Ugi-4CR/ring-closing metathesis/Heck reaction strategy (Scheme [59]). Initially, the four-component Ugi reaction between different aldehydes, an amine, a carboxylic acid, and isopropyl isocyanide was carried out to give diene Ugi adducts 254 in moderate to excellent yields, which underwent ring-closing metathesis in the presence of the Grubbs second-generation catalyst to give unsaturated δ-lactams 255 in excellent yields. Subsequent intramolecular Heck reaction of 255 using two different Pd catalysts [Pd(PPh₃)₂Cl₂ or FibreCat 1032] resulted in the formation of complex bridged bicyclic δ-lactams 253a–c and ε-lactams 253d,e. It was noted that the Heck reaction was well tolerated and equally efficient in the presence of both catalysts.

Akritopoulou-Zanze’s group[102] reported the synthesis of polycyclic fused δ-lactams 258 via a two-step Ugi-4CR of chromenone acetic acid 256, aldehydes or ketones, amines, and isopropyl isocyanide to initially give Ugi adducts 257. This was followed by a [2+2] enone–alkene photochemical cycloaddition in MeOH using a 450 W mercury lamp (Scheme [60]). Using dihydroquinoline acetic acid instead of acid 256, the authors were able to easily prepare polycyclic fused bis-δ-lactam 259 in 87% yield. Switching the acid source 256 to oxo-cyclohexene acid 260 and the substituted allylamine to long-chain amines resulted in the formation of tricyclic fused γ-, δ- and ε-lactams 261 in excellent yields.

2.5

ε-Lactams

Scheme 61 Synthesis of ε-lactams 263

Foroumadi and colleagues[103] reported the synthesis of ε-lactams 263 by employing 6-aminohexanoic acid (262), aldehydes, and isocyanides in Ugi-3CRs in water under reflux conditions for 18–24 hours (Scheme [61]). It was noted that no product formation was observed when the reactions were performed at ambient temperature. ortho-Methyl-substituted benzaldehyde gave the lowest yield (10%), suggesting that steric effects play an important role in the reaction. The mild and green reaction conditions are advantages of this methodology.

In 2017, Balalaie and co-workers[104] reported the diversity-oriented synthesis of isoxazolino- and isoxazolo-fused ε-lactams 266 and 268 via a one-pot Ugi-4CR followed by an intramolecular 1,3-dipolar cycloaddition (Scheme [62]). It was demonstrated that the four-component reaction between functionalized acid 264, an aldehyde, an isocyanide, and either allylamine or propargylamine in MeOH at ambient temperature gave the Ugi adducts 265 or 267, respectively. Subsequently, intramolecular 1,3-dipolar cycloaddition resulted in the formation of ε-lactams 266 and 268 in good to excellent yields. It was noted that all the synthesized ε-lactams were obtained with high diastereoselective ratios.

Scheme 62 Synthesis of isoxazolino- and isoxazolo-fused ε-lactams 266 and 268

Riva and co-workers[105] have reported the synthesis of fused polycyclic natural-product-like molecules 272 containing a 7-membered lactam core via an Ugi-4CR/S_N2 cyclization/Heck reaction methodology (Scheme [63]). The Ugi adducts 270 were prepared in excellent yields (72–96%) by reacting aldehydes, polyfunctionalized isocyanide 269, amines, and acids in a mixture of trifluoroethanol–ethanol (1:1) . Next, the adducts 270 were readily converted into compounds 271 in quantitative yields via intramolecular S_N2 carbocyclization using a Pd(PPh₃)₄–DPPE catalytic system. Subsequently, a microwave-assisted Pd-catalyzed intramolecular Heck reaction afforded the fused polycyclic lactams 272 in poor to excellent yields (0–81%). It was noted that the nature of the halogen atom on the aldehyde influenced the Heck cyclization. When iodo derivatives were used, the cyclization was cleaner and high yielding compared to the bromo derivatives. Also, it was reported that a one-pot S_N2/Heck cyclization sequence gave comparable yields of lactams 272 (from Ugi adducts 270) to those obtained via the two-step method.

Scheme 63 Synthesis of fused polycyclic seven-membered lactams 272

In 2013, Gámez-Montaño and co-workers[106] reported the synthesis of 1,5-disubstituted-tetrazole-linked polycyclic ε-lactams 274 in moderate to excellent yields via a two-step Ugi-4CR/N-acylation/S_N2 strategy, followed by an intramolecular radical cyclization (Scheme [64]). Initially, an Ugi-4CR between tryptamine (179), aldehydes, isocyanides, and TMSN₃ was followed by the addition of KSC(S)OEt to give Ugi xanthate adducts 273, which on radical cyclization afforded ε-lactams 274. All the reactions gave comparable yields of 274 when performed using two different conditions, i.e., conventional heating and microwave irradiation. It was proposed, based on docking studies, that these synthesized compounds could inhibit the 5-Ht₆ protein and thus might be useful in the discovery of anti-Alzheimer drugs. Later, in 2016, the same researchers[107] demonstrated the synthesis of amide-linked ε-lactams 276, as bioisosteres of 1,5-disubstituted tetrazole lactams 274, via Ugi-4CR/S_N2/radical cyclization under similar reaction conditions. The authors performed a comparative protein-binding affinity study between the two lactam series with the help of computational calculations, which suggested that lactams 276 showed a slight increased binding affinity towards the 5-Ht₆R protein compared to lactams 274.

Scheme 64 Synthesis of polycyclic ε-lactams 274 and 276

In 2011, Van der Eycken and co-workers[108] reported the diastereoselective synthesis of biaryl-fused ε-lactams 278 via an intramolecular four-centered Ugi-3CR by using bifunctional biaryls 277 (Scheme [65]). A multicomponent reaction between 2′-formylbiphenyl-2-carboxylic acids 277, amines and isocyanides in the presence of sodium sulfate in 2,2,2-trifluoroethanol at 110 °C under microwave irradiation afforded the ε-lactams 278 in moderate to quantitative yields (40–99%). The authors demonstrated 37 examples of this methodology including the synthesis of ε-lactam 278a when phenylhydrazine was used as the amine input. Further, when the chiral amines (S)-(+)-2-phenylglycine methyl ester and l-leucinol were used, ε-lactams 278b and 278c were obtained in 64% and 40% yields, respectively, both with 1:1 diastereomeric ratios. All the synthesized compounds were screened against various DNA and RNA viruses, however, none of them were found to be active. Further, when the same series was tested for their antiproliferative activity, several promising compounds were found to be active against tumor cell lines in the lower micromolar range.

Scheme 65 Synthesis of biaryl-fused ε-lactams 278 via an intramolecular Ugi-IMCR

3

Conclusions

In conclusion, this review has summarized the advances made in the synthesis of lactams via isocyanide-based multicomponent reactions (IMCRs) in the last two decades. Huge progress has been accomplished in the synthesis of simple, highly substituted, unsaturated, polycyclic, fused and spiro lactams since the discovery of the β-lactam-containing antibiotic penicillin. However, there are several improvements that are still desired in this area. (1) The most useful reports on the synthesis of benzo-fused or polycyclic lactams via C–N or C–H functionalization are largely dependent on expensive Pd or Au catalysts, hence, the development of new and inexpensive metal catalysts is required. (2) Despite α- and ε-lactam motifs being found in various bioactive molecules and natural products, there are only a few synthetic methods available via IMCRs. Thus, significant further developments towards their synthesis are required. (3) Most of the IMCR/post-transformation strategies often require high temperatures, long reaction times, and non-green conditions. Therefore, the development of mild, short, and eco-friendly reaction conditions is highly desirable. (4) IMCR or IMCR/post-transformation methodologies yielding asymmetric lactams are rare. Hence, the development of efficient asymmetric approaches towards chiral lactam analogues remains an important challenge.

• References

• 1 Fleming A. Br. J. Exp. Pathol. 1929; 10: 226
• 2a Shahid M, Sobia F, Singh A, Malik A, Khan HM, Jonas D, Hawkey PM. Crit. Rev. Microbiol. 2009; 35: 81
• 2b Kapoor G, Saigal S, Elongavan A. J. Anaesthesiol. Clin. Pharmacol. 2017; 33: 300
• 2c Tahlan K, Jensen SE. J. Antibiot. 2013; 66: 401
• 3a Kerru N, Gummidi L, Maddila S, Gangu KK, Jonnalagadda SB. Molecules 2020; 25: 1909
• 3b Alborz M, Jarrahpour A, Pournejati R, Karbalaei-Heidari HR, Sinou V, Latour C, Brunel JM, Sharghi H, Aberi M, Turos E, Wojtas L. Eur. J. Med. Chem. 2018; 143: 283
• 3c Matviiuk T, Madacki J, Mori G, Orena BS, Menendez C, Kysil A, André-Barrès C, Rodriguez F, Korduláková J, Mallet-Ladeira S, Voitenko Z, Pasca MR, Lherbet C, Baltas M. Eur. J. Med. Chem. 2016; 123: 462
• 3d Medvedeva NI, Kazakova OB, Lopatina TV, Smirnova IE, Giniyatullina GV, Baikova IP, Kataev VE. Eur. J. Med. Chem. 2018; 143: 464
• 4a Gao M, Glenn AE, Blacutt AA, Gold SE. Front. Microbiol. 2017; 8: 1775
• 4b Delong W, Lanying W, Yongling W, Shuang S, Juntao F, Xing Z. Eur. J. Med. Chem. 2017; 130: 286
• 5 Rad JA, Jarrahpour A, Latour C, Sinou V, Brunel JM, Zgou H, Mabkhot Y, Hadda TB, Turos T. Med. Chem. Res. 2017; 26: 2235
• 6a Sperka T, Pitlik J, Bagossi P, Tözsér J. Bioorg. Med. Chem. Lett. 2005; 15: 3086
• 6b Chang Y.-CE, Yu X, Zhang Y, Tie Y, Wang YF, Yashchuk S, Ghosh AK, Harrison RW, Weber IT. J. Med. Chem. 2012; 55: 3387
• 7a O’Boyle NM, Carr M, Greene LM, Bergin O, Nathwani SM, McCabe T, Lloyd DG, Zisterer DM, Meegan MJ. J. Med. Chem. 2010; 53: 8569
• 7b Hardcastle IR, Liu J, Valeur E, Watson A, Ahmed SU, Blackburn TJ, Bennaceur K, Clegg W, Drummond C, Endicott JA, Golding BT, Griffin RJ, Gruber J, Haggerty K, Harrington RW, Hutton C, Kemp S, Lu X, McDonnell JM, Newell DR, Noble ME. M, Payne SL, Revill CH, Riedinger C, Xu Q, Lunec J. J. Med. Chem. 2011; 54: 1233
• 7c Rew Y, Sun D. J. Med. Chem. 2014; 57: 6332
• 7d Jane deSolms S, Ciccarone TM, MacTough SC, Shaw AW, Buser CA, Ellis-Hutchings M, Fernandes C, Hamilton KA, Huber HE, Kohl NE, Lobell RB, Robinson RG, Tsou NN, Walsh ES, Graham SL, Beese LS, Taylor JS. J. Med. Chem. 2003; 46: 2973
• 8a Saturnino C, Fusco B, Saturnino P, Martino GD. E, Rocco F, Lancelot J.-C. Biol. Pharm. Bull. 2000; 23: 654
• 8b Okumura K, Inoue I, Ikezaki M, Hayashi G, Nurimoto S, Shintomi K. J. Med. Chem. 1966; 9: 315
• 9 Gillard K, Miller HB, Blackledge MS. Chem. Biol. Drug Des. 2018; 92: 1822
• 10 Atigadda VR, Brouillette WJ, Duarte F, Ali SM, Babu YS, Bantia S, Chand P, Chu N, Montgomery JA, Walsh DA, Sudbeck EA, Finley J, Luo M, Air GM, Laver GW. J. Med. Chem. 1999; 42: 2332
• 11 Pei Z, Li X, von Geldern TW, Longenecker K, Pireh D, Stewart KD, Backes BJ, Lai C, Lubben TH, Ballaron SJ, Beno DW. A, Kempf-Grote AJ, Sham HL, Trevillyan JM. J. Med. Chem. 2007; 50: 1983
• 12a Reddy PA, Woodward KE, McIlheran SM, Hsiang BC. H, Latifi TN, Hill MW, Rothman SM, Ferrendelli JA, Covey DF. J. Med. Chem. 1997; 40: 44
• 12b Brouillettet WJ, Grunewald GL. J. Med. Chem. 1984; 27: 202
• 13a Royles BJ. L. Chem. Rev. 1995; 95: 1981
• 13b Davidson BS, Schumacher RW. Tetrahedron 1993; 49: 6569
• 13c Garcia-Ruiz C, Sarabia F. Mar. Drugs 2014; 12: 1580
• 13d He Q, Chatani N. J. Org. Chem. 2018; 83: 13587
• 13e Davies SG, Roberts PM, Smith AD. Org. Biomol. Chem. 2007; 5: 1405
• 13f Tikhov R, Kuznetsov NY. Org. Biomol. Chem. 2020; 18: 2793
• 13g Saldívar-González FI, Lenci E, Trabocchi A, Medina-Franco JL. RSC Adv. 2019; 9: 27105
• 14 Fernandes R, Amador P, Prudencio C. Rev. Med. Microbiol. 2013; 24: 7
• 15a Baldwin JE, Lowe C, Schofield CJ, Lee E. Tetrahedron Lett. 1986; 27: 3461
• 15b Boyd DB, Elzey TK, Hatfield LD, Kinnick MD, Morin JM. Jr. Tetrahedron Lett. 1986; 27: 3453
• 16 Mohammadkhani L, Heravi MM. ChemistrySelect 2019; 4: 10187
• 17a Passerini M. Gazz. Chim. Ital. 1921; 51: 126
• 17b Passerini M. Gazz. Chim. Ital. 1921; 51: 181
• 18 Ugi I, Meyr R, Fetzer U, Steinbruckner C. Angew. Chem. 1959; 71: 386
• 19a Ugi I. Angew. Chem., Int. Ed. Eng. 1962; 1: 8 ; Angew. Chem. 1962, 74, 9
• 19b Ugi I, Steinbruckner C. Chem. Ber. 1961; 94: 2802
• 20a Multicomponent Reactions . Zhu J, Bienaymé H. Wiley-VCH; Weinheim: 2005
• 20b Domling A, Ugi I. Angew. Chem. Int. Ed. 2000; 39: 3168
• 21 Cesare V, Lyons TM, Lengyel I. Synthesis 2002; 1716
• 22 Liu N, Cao S, Wu J, Shen L, Yu J, Zhang J, Li H, Qian X. Mol. Diversity 2010; 14: 501
• 23 Zeng X.-H, Wang H.-M, Yan Y.-M, Wu L, Ding M.-W. Tetrahedron 2014; 70: 3647
• 24 Gao X, Shan C, Chen Z, Liu Y, Zhao X, Zhang A, Yu P, Galons H, Lan Y, Lu K. Org. Biomol. Chem. 2018; 16: 6096
• 25 Santra S, Andreana PR. Org. Lett. 2007; 9: 5035
• 26 Neochoritis CG, Stotani S, Mishra B, Dömling A. Org. Lett. 2015; 17: 2002
• 27 Schneider G, Neidhart W, Giller T, Schmid G. Angew. Chem. Int. Ed. 1999; 38: 2894
• 28 Czarna A, Beck B, Srivastava S, Popowicz GM, Wolf S, Huang Y, Bista M, Holak TA, Dömling A. Angew. Chem. Int. Ed. 2010; 49: 5352
• 29 Shaabani S, Neochoritis CG, Twarda-Clapa A, Musielak B, Holak TA, Dömling A. Med. Chem. Commun. 2017; 8: 1046
• 30 Blackie MA. L, Feng T.-S, Smith PJ, Chibale K. ARKIVOC 2016; (iii): 214
• 31 Avilés E, Rodríguez AD. Org. Lett. 2010; 12: 5290
• 32 Wratten SJ, Faulkner DJ, Hirotsu K, Clardy J. Tetrahedron Lett. 1978; 19: 4345
• 33 Rainoldi G, Lesma G, Picozzi C, Presti LL, Silvani A. RSC Adv. 2018; 8: 34903
• 34 Madej A, Paprocki D, Koszelewski D, Żądło-Dobrowolska A, Brzozowska A, Walde P, Ostaszewski R. RSC Adv. 2017; 7: 33344
• 35 Pirrung MC, Sarma KD. J. Am. Chem. Soc. 2004; 126: 444
• 36 Pirrung MC, Sarma KD. Synlett 2004; 1425
• 37 Kanizsai I, Gyónfalvi S, Szakonyi Z, Sillanpää R, Fülöp F. Green Chem. 2007; 9: 357
• 38a Gedey S, Van der Eycken J, Fülöp F. Org. Lett. 2002; 4: 1967
• 38b Gedey S, Fülöp F, Vainiotalo P, De Witte PA. M, Zupkó I. J. Heterocycl. Chem. 2003; 40: 951
• 39 Szakonyi Z, Sillanpää R, Fülöp F. Mol Diversity 2010; 14: 59
• 40a Basavaiah D, Rao AJ, Satyanarayana T. Chem. Rev. 2003; 103: 811
• 40b Lin A, Mao H, Zhu X, Ge H, Tan R, Zhu C, Cheng Y. Chem. Eur. J. 2011; 17: 13676
• 41 Li Z, Sharma UK, Liu Z, Sharma N, Harvey JN, Van der Eycken EV. Eur. J. Org. Chem. 2015; 3957
• 42 Ghabraie E, Balalaie S, Mehrparvar S, Rominger F. J. Org. Chem. 2014; 79: 7926
• 43a Ramanivas T, Parameshwar M, Gayatri G, Nanubolu JB, Srivastava AK. Eur. J. Org. Chem. 2017; 2245
• 43b Ghoshal A, Kumar A, Yugandhar D, Sona C, Kuriakose S, Nagesh K, Rashid M, Singh SK, Wahajuddin M, Yadav PN, Srivastava AK. Eur. J. Med. Chem. 2018; 152: 148
• 44 Fan L, Adams AM, Polisar JG, Ganem B. J. Org. Chem. 2008; 73: 9720
• 45 Zidan A, Garrec J, Cordier M, El-Naggar AM, Abd El-Sattar NE. A, Ali AK, Ali Hassan M, El Kaim L. Angew. Chem. Int. Ed. 2017; 56: 12179
• 46 Cheibas C, Cordier M, Li Y, El Kaïm L. Eur. J. Org. Chem. 2019; 4457
• 47 Tye H, Whittaker M. Org. Biomol. Chem. 2004; 2: 813
• 48 Harriman GC. B. Tetrahedron Lett. 1997; 38: 5591
• 49 Mironov MA, Ivantsova MN, Mokrushin VS. Mol. Diversity 2003; 6: 193
• 50 Jida M, Malaquin S, Deprez-Poulain R, Laconde G, Deprez D. Tetrahedron Lett. 2010; 51: 5109
• 51 Krelaus R, Westermann B. Tetrahedron Lett. 2004; 45: 5987
• 52a Lyseng-Williamson KA. Drugs 2011; 71: 489
• 52b Malykh AG, Sadaie MR. Drugs 2010; 70: 287
• 52c Gualtieri F, Manetti D, Romanelli MN, Ghelardini C. Curr. Pharm. Des. 2002; 8: 125
• 52d Genton P, Van Vleymen B. Epileptic Disord. 2000; 2: 99
• 53 Cioc RC, Schaepkens van Riempst L, Schuckman P, Ruijter E, Orru RV. A. Synthesis 2017; 49: 1664
• 54 Echeverria V. Front. Pharmacol. 2012; 3: 173
• 55 Polindara-García LA, Montesinos-Miguel D, Vazquez A. Org. Biomol. Chem. 2015; 13: 9065
• 56 Shiri M, Mirpour-Marzoni SZ, Bozorgpour-Savadjani Z, Soleymanifard B, Kruger HG. Monatsh. Chem. 2014; 145: 1947
• 57 Gunawan S, Petit J, Hulme C. ACS Comb. Sci. 2012; 14: 160
• 58 Gil C, Bräse S. J. Comb. Chem. 2009; 11: 175
• 59 Liu Z, Nefzi A. J. Comb. Chem. 2010; 12: 566
• 60 El Kaïm L, Grimaud L, Miranda LD, Vieu E. Tetrahedron Lett. 2006; 47: 8259
• 61 El Kaïm L, Grimaud L, Miranda LD, Vieu E, Cano-Herrera M.-A, Perez-Labrada K. Chem. Commun. 2010; 46: 2489
• 62 Zidan A, Cordier M, El-Naggar AM, Abd El-Sattar NE. A, Hassan MA, Ali AK, El Kaïm L. Org. Lett. 2018; 20: 2568
• 63 Boltjes A, Liao GP, Zhao T, Herdtweck E, Dömling A. Med. Chem. Commun. 2014; 5: 949
• 64 Borja-Miranda A, Sanchez-Chavez AC, Polindara-García LA. Eur. J. Org. Chem. 2019; 2453
• 65 Khan IA, Saxena AK. Tetrahedron 2012; 68: 294
• 66 Bonnaterre F, Bois-Choussy M, Zhu J. Org. Lett. 2006; 8: 4351
• 67 Erb W, Neuville L, Zhu J. J. Org. Chem. 2009; 74: 3109
• 68 Lei J, Xu Z.-G, Li S.-Q, Xu J, Zhu J, Chen Z.-Z. Mol Diversity 2016; 20: 859
• 69a Zard SZ. Acc. Chem. Res. 2018; 51: 1722
• 69b Rentería-Gómez A, Islas-Jácome A, Jiménez-Halla JO. C, Gámez-Montaño R. Tetrahedron Lett. 2014; 55: 6567
• 70 Umkehrer M, Kalinski C, Kolb J, Burdack C. Tetrahedron Lett. 2006; 47: 2391
• 71 Bararjanian M, Hosseinzadeh S, Balalaie S, Bijanzadeh HR, Wolf E. Tetrahedron Lett. 2011; 52: 3329
• 72 Butler RN. In Comprehensive Heterocyclic Chemistry II, Vol. 4. Katritzky AR, Rees CW, Scriven EF. V. Pergamon; Oxford: 1996: 621
• 73 Marcos CF, Marcaccini S, Menchi G, Pepino R, Torroba T. Tetrahedron Lett. 2008; 49: 149
• 74 Gunawan S, Hulme C. Org. Biomol. Chem. 2013; 11: 6036
• 75 Rentería-Gómez A, Islas-Jácome A, Cruz-Jiménez AE, Manzano-Velázquez JC, Rojas-Lima S, Jiménez-Halla JO. C, Gámez-Montaño R. ACS Omega 2016; 1: 943
• 76 Salcedo A, Neuville L, Zhu J. J. Org. Chem. 2008; 73: 3600
• 77 García-González MC, Hernández-Vázquez E, Gordillo-Cruz RE, Miranda LD. Chem. Commun. 2015; 51: 11669
• 78 Maddirala AR, Andreana PR. Beilstein J. Org. Chem. 2018; 14: 875
• 79 Ghandi M, Zarezadeh N, Abbasi A. Org. Biomol. Chem. 2015; 13: 8211
• 80 Stolyarenko VY, Evdokimov AA, Shishkin VI. Mendeleev Commun. 2013; 23: 108
• 81 Gámez-Montaño R, Ibarra-Rivera T, El Kaïm L, Miranda LD. Synthesis 2010; 1285
• 82 Alvarez-Rodríguez NV, Islas-Jácome A, Rentería-Gomez A, Cárdenas-Galindo LE, Basavanaga UM. V, Gámez-Montaño R. New J. Chem. 2018; 42: 1600
• 83 Touré BB, Hall DG. Chem. Rev. 2009; 109: 4439
• 84 Schultz EE, Pujanauski BG, Sarpong R. Org. Lett. 2012; 14: 648
• 85a Keating TA, Armstrong RW. J. Am. Chem. Soc. 1995; 117: 7842
• 85b van der Heijden G, Jong JA. W, Ruijter E, Orru RV. A. Org. Lett. 2016; 18: 984
• 86 Nagasaka Y, Shintaku S, Matsumura K, Masuda A, Asakawa T, Inai M, Egi M, Hamashima Y, Ishikawa Y, Kan T. Org. Lett. 2017; 19: 3839
• 87 Ku IW, Kang SB, Keum G, Kim Y. Bull. Korean Chem. Soc. 2011; 32: 3167
• 88 Alvarez-Rodríguez NV, Dos Santos A, El Kaïm L, Gámez-Montaño R. Synlett 2015; 26: 2253
• 89 Peshkov AA, Peshkov VA, Li Z, Pereshivko OP, Van der Eycken EV. Eur. J. Org. Chem. 2014; 6390
• 90 Li Z, Kumar A, Peshkov A, Van der Eycken EV. Tetrahedron Lett. 2016; 57: 754
• 91 Yugandhar D, Kuriakose S, Nanubolu JB, Srivastava AK. Org. Lett. 2016; 18: 1040
• 92 Li Z, Zhao Y, Tian G, He Y, Song G, Meervelt LV, Van der Eycken EV. RSC Adv. 2016; 6: 103601
• 93 Gordon CP, Young KA, Robertson MJ, Hill TA, McCluskey A. Tetrahedron 2011; 67: 554
• 94 Santra S, Andreana PR. Angew. Chem. Int. Ed. 2011; 50: 9418
• 95 Ilyin A, Kysil V, Krasavin M, Kurashvili I, Ivachtchenko AV. J. Org. Chem. 2006; 71: 9544
• 96 Kumar A, Vachhani DD, Modha SG, Sharma SK, Parmar VS, Van der Eycken EV. Beilstein J. Org. Chem. 2013; 9: 2097
• 97 Gunawan S, Keck K, Laetsch A, Hulme C. Mol. Diversity 2012; 16: 601
• 98 Akritopoulou-Zanze I, Gracias V, Moore JD, Djuric SW. Tetrahedron Lett. 2004; 45: 3421
• 99 Gracias V, Moore JD, Djuric SW. Tetrahedron Lett. 2004; 45: 417
• 100 Vachhani DD, Galli M, Jacobs J, Van Meervelt L, Van der Eycken EV. Chem. Commun. 2013; 49: 7171
• 101 Ribelin TP, Judd AS, Akritopoulou-Zanze I, Henry RF, Cross JL, Whittern DN, Djuric SW. Org. Lett. 2007; 9: 5119
• 102 Akritopoulou-Zanze I, Whitehead A, Waters JE, Henry RF, Djuric SW. Org. Lett. 2007; 9: 1299
• 103 Rasouli MA, Mahdavi M, Ranjbar PR, Saeedi M, Shafiee A, Foroumadi A. Tetrahedron Lett. 2012; 53: 7088
• 104 Balalaie S, Shamakli M, Nikbakht A, Alavijeh NS, Rominger F, Rostamizadeh S, Bijanzadeh HR. Org. Biomol. Chem. 2017; 15: 5737
• 105 Riva R, Banfi L, Basso A, Cerulli V, Guanti G, Pani M. J. Org. Chem. 2010; 75: 5134
• 106 Gordillo-Cruz RE, Rentería-Gómez A, Islas-Jácome A, Cortes-García CJ, Díaz-Cervantes E, Robles J, Gámez-Montaño R. Org. Biomol. Chem. 2013; 11: 6470
• 107 Rentería-Gómez A, Islas-Jácome A, Díaz-Cervantes E, Villaseñor-Granados T, Robles J, Gámez-Montaño R. Bioorg. Med. Chem. Lett. 2016; 26: 2333
• 108 Mehta VP, Modha SG, Ruijter E, Van Hecke K, Van Meervelt L, Pannecouque C, Balzarini J, Orru RV. A, Van der Eycken E. J. Org. Chem. 2011; 76: 2828

Publikationsverlauf

Eingereicht: 16. Mai 2020

Angenommen nach Revision: 22. August 2020

Artikel online veröffentlicht:
07. Oktober 2020